In This Issue

FEATURE ARTICLES, BIOCHEMISTRY

Intricate choreography of cholesterol metabolism

Cholesterol is an essential component of cell membranes that regulates the fluidity of membranes and helps to coordinate signaling events. However, high levels of cholesterol bound to low-density lipoprotein increase the risk of heart disease. Therefore, cholesterol metabolism has to be tightly regulated. Arun Radhakrishnan et al. and Li-Ping Sun et al. examined how cholesterol synthesis is regulated at the molecular level. Radhakrishnan et al. studied cholesterol derivatives called oxysterols that are involved in the feedback mechanism that inhibits cholesterol synthesis. Using in vitro binding assays and mutagenesis experiments, the authors showed that oxysterols bind to the protein Insig, which is known to be part of the feedback loop inhibiting cholesterol synthesis. Li-Ping Sun et al. investigated how the binding of cholesterol or oxysterols to their respective receptors activates the mechanism that prevents further cholesterol synthesis. The authors focused on the protein Scap, which escorts sterol regulatory element-binding proteins that are involved in switching on cholesterol synthesis genes when cellular cholesterol levels are low. Based on in vivo and in vitro accessibility studies, the authors developed a model of how Scap changes its conformation in the presence versus the absence of cholesterol or oxysterols. — F.H.

“Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig” by Arun Radhakrishnan, Yukio Ikeda, Hyock Joo Kwon, Michael S. Brown, and Joseph L. Goldstein (see pages 6511–6518)

and

“Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins” by Li-Ping Sun, Joachim Seemann, Joseph L. Goldstein, and Michael S. Brown (see pages 6519–6526)

GEOLOGY

Runoff contributes to climate change

Anders Carlson et al. have found evidence that the Younger Dryas cold event was caused by increased freshwater runoff from western Canada flowing into the Atlantic Ocean. Their finding provides support for the hypothesis that freshwater runoff caused the abrupt climatic change. The authors used several geochemical proxies to measure deglacial freshwater runoff at the mouth of the St. Lawrence river. They measured trace element concentrations and isotope ratios in columns of planktonic foraminifera and compared them with river geochemistry throughout North America to determine the sources of the freshwater incorporated by the plankton in the past. Their analysis indicates that freshwater runoff increased at the beginning of the Younger Dryas, 12,900 years ago. Carlson et al. say that this discharge increase was enough to have reduced Atlantic meridional overturning circulation and caused the Younger Dryas cold event, and found that the flow increased and fluctuated enough to cause the climate variations that occurred during the cold event. The authors say their results imply that freshwater runoff is a contributor to abrupt climate change. — P.D.

“Geochemical proxies of North American freshwater routing during the Younger Dryas cold event” by Anders E. Carlson, Peter U. Clark, Brian A. Haley, Gary P. Klinkhammer, Kathleen Simmons, Edward J. Brook, and Katrin J. Meissner (see pages 6556–6561)

APPLIED BIOLOGICAL SCIENCES

Multiple protein knockdown by RNA interference

The discovery of RNA interference by Andrew Z. Fire and Craig C. Mello, honored with the 2006 Nobel Prize in Physiology or Medicine, gives researchers the ability to reduce expression of individual proteins. Upon exposure to siRNAs, short pieces of single-stranded RNA, cells assemble an siRNA–protein complex that destroys mRNAs complementary to the siRNAs, preventing translation of the mRNAs and reducing expression of the encoded protein. Özgür Sahin et al. tested whether siRNAs targeting different proteins can be used in combination to simultaneously reduce expression of three proteins involved in tumor invasion. The authors assayed the effectiveness and specificity of the single, double, and triple knockdown at the mRNA and protein levels. Low concentrations of siRNA reduced expression of the targeted proteins by >60% while keeping expression of nontargeted proteins constant. At higher concentrations of siRNA, specific knockdown did not necessarily increase; however, expression of several proteins not targeted by the siRNAs decreased. After optimizing delivery of siRNAs targeting the signaling proteins ErbB2, Akt1, and MEK1, the authors measured invasivity of tumor cells with reduced expression of one, two, or all three of these proteins. — F.H.

“Combinatorial RNAi for quantitative protein network analysis” by Özgür Sahin, Christian Löbke, Ulrike Korf, Heribert Appelhans, Holger Sültmann, Annemarie Poustka, Stefan Wiemann, and Dorit Arlt (see pages 6579–6584)

IMMUNOLOGY

Linking cancer and inflammation

Epithelial cells act as the front line between the body and the outside world, constantly battling external insults, resulting in chronic inflammation. Because of their high turnover rate, these cells are primed for the genetic damage that leads to cancer. Scott Roberts et al. investigated the long-standing link between chronic inflammation and cancer in a mouse model system. Previous research showed that mice depleted of T cells are more resistant to chemically induced carcinogenesis, but it was unclear whether the T cells actively promoted tumor formation or simply prevented an optimal antitumor response. Roberts et al. found that mice lacking CD8⁺ T cells were more resistant to carcinogenesis. The authors isolated and characterized a population of CD8⁺ T cells from the tumor area. The T cells produced inflammatory cytokines and showed similar properties to other cells associated with facilitating tissue growth. Identifying cells that drive the inflammatory process during carcinogenesis is important in attempting to ameliorate it. — T.H.D.

“Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis” by Scott J. Roberts, Bernice Y. Ng, Renata B. Filler, Julia Lewis, Earl J. Glusac, Adrian C. Hayday, Robert E. Tigelaar, and Michael Girardi (see pages 6770–6775)

NEUROSCIENCE

Feedback loop for cardiac response to stress

Emotional stress, particularly in people with underlying heart conditions, can cause cardiac arrhythmias and sudden death, primarily through the sympathetic nervous system acting on heart tissue. However, research has suggested that the cortex, the seat of higher cognitive function, also receives incoming information from the heart and may participate in a feedback loop that can amplify stress-induced cardiac events. Marcus Gray et al. examined this feedback mechanism by asking patients with a preexisting heart condition to perform a mildly stressful task known to raise heart rate: counting backward rapidly by sevens. The authors then measured the simultaneous changes in cardiac response and brain activity. Although all patients experienced enhanced cardiovascular activity (e.g., systolic blood pressure, heart rate), measures of myocardium function varied between patients. In addition, these functional changes correlated with increased activity in the left temporal and lateral frontal cortex, where adjacent activity also predicted risk of cardiac arrhythmias. The study demonstrates that the cortex participates in a feedback loop that regulates cardiac response to stress, and this mechanism may provide insight into stress-induced cardiac arrhythmias and sudden death in people with underlying heart conditions. — M.M.

“A cortical potential reflecting cardiac function” by Marcus A. Gray, Peter Taggart, Peter M. Sutton, David Groves, Diana R. Holdright, David Bradbury, David Brull, and Hugo D. Critchley (see pages 6818–6823)